rs876658502

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000051.4(ATM):​c.3085dupA​(p.Thr1029AsnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 0.199
Variant links:
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108272537-T-TA is Pathogenic according to our data. Variant chr11-108272537-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 230318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.3085dupA p.Thr1029AsnfsTer19 frameshift_variant Exon 21 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.3085dupA p.Thr1029AsnfsTer19 frameshift_variant Exon 21 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459460
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726260
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3
Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 18, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ATM c.3085dupA (p.Thr1029AsnfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3245_3247delinsTGAT (p.His1082fsX14), c.3712_3716delTTATT (p.Leu1238fsX6)). The variant was absent in 246070 control chromosomes (gnomAD) but has been reported in the literature in multiple compound heterozygous individuals affected with Ataxia-Telangiectasia (Keimling_2011, Micol_2011, Mitui_2005, Sandoval_1999, Teraoka_1999). These data indicate that the variant is very likely to be associated with disease. One publication reported the complete absence of ATM protein (analyzed by western blotting) in a lymphoblastoid cell line (LCL) derived from a patient who was compound heterozygote for this variant and another truncating ATM variant (Keimling_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr1029Asnfs*19) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia telangiectasia (PMID: 9443866, 9887333, 10330348, 16266405, 29665859). This variant is also known as 3084insA, 3085insA, 3085_3086insA. ClinVar contains an entry for this variant (Variation ID: 230318). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3
Apr 18, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in the heterozygous state in a patient with breast cancer (PMID: 29665859); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 9887333, 9443866, 10330348, 16266405, 30612635, 37149759, 29665859) -

Apr 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ATM: PVS1, PM2, PS4:Moderate -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3
Jun 20, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 21 of the ATM gene (also known as 3084insA, 3085insA, 3085_3086insA), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 9443866, 16266405, 10330348, 9887333). Additionally, it has been reported in an individual affected with breast cancer (PMID: 29665859) and an individual affected with anaplastic astrocytoma (PMID: 37149759). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Jan 23, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3085dupA pathogenic mutation, located in coding exon 20 of the ATM gene, results from a duplication of A at nucleotide position 3085, causing a translational frameshift with a predicted alternate stop codon (p.T1029Nfs*19). This mutation (also designated as c.3085_3086insA) has been reported in numerous individuals with Ataxia-Telangiectasia (A-T) (Telatar M et al. Am. J. Hum. Genet. 1998 Jan; 62(1):86-97; Teraoka S et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31; Sandoval N et al. Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Mitui M et al. Ann. Hum. Genet. 2005 Nov; 69(Pt 6):657-64). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

-
Hauer Lab, Department Of Pediatric Oncology, Technical University Munich
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

ACMG/AMP, PVS1, PM2, PP5 -

Familial cancer of breast Pathogenic:2
Jan 18, 2024
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Jan 17, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
Mar 21, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ATM-related disorder Pathogenic:1
Aug 03, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ATM c.3085dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr1029Asnfs*19). This variant has been reported in individuals with ataxia telangiectasia (Table 2, referred to as c.3084insA, Telatar et al. 1998. PubMed ID: 9443866; Table 1, Sandoval et al. 1999. PubMed ID: 9887333; Table 2, Teraoka et al. 1999. PubMed ID: 10330348; Mitui et al. 2005. PubMed ID: 16266405; Table E1, Micol et al. 2011. PubMed ID: 21665257;). It has also been reported in an individual with breast cancer (Table 1, Renault et al. 2018. PubMed ID: 29665859). In vitro experimental studies indicate this variant impairs protein expression (Figure 1 and Table 1, Keimling et al. 2011. PubMed ID: 21778326). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230318/). This variant is interpreted pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876658502; hg19: chr11-108143264; API